Supramolecular 3 in 1: A Lubrication and Co-Delivery System for Synergistic Advanced Osteoarthritis Therapy.

The complexity, heterogeneity, and drug resistance of diseases necessitate a shift in therapeutic paradigms from monotherapy to combination therapy, which could augment treatment efficiency. Effective treatment of advanced osteoarthritis (OA) requires addressing three key factors contributing to its deterioration: chronic joint inflammation, lubrication dysfunction, and cartilage-tissue degradation. Herein, we present a supramolecular nanomedicine of multifunctionality via molecular recognition and self-assembly. The employed macrocyclic carrier, zwitterion-modified cavitand (CV-2), not only accurately loads various drugs but also functions as a therapeutic agent with lubricating properties for the treatment of OA. Kartogenin (KGN), a drug for articular cartilage regeneration and protection, and flurbiprofen (FP), an anti-inflammatory agent, were coloaded onto CV-2 assembly, forming a supramolecular nanomedicine KGN&FP@CV-2. The three-in-one combination therapy of KGN&FP@CV-2 addresses the three pathological features for treating OA collectively, and thus provides long-term therapeutic benefits for OA through sustained drug release and intrinsic lubrication in vivo. The multifunctional integration of macrocyclic delivery and therapeutics provides a simple, flexible, and universal platform for the synergistic treatment of diseases involving multiple drugs.

Enantiopure Corral[4]BINOLs as Ultrastrong Receptors for Recognition and Differential Sensing of Steroids.

The precise recognition and sensing of steroids, a type of vital biomolecules, hold immense practical value across various domains. In this study, we introduced corral[4]BINOLs (C[4]BINOLs), a pair of enantiomeric conjugated deep-cavity hosts, as novel synthetic receptors for binding steroids. Due to the strong hydrophobic effect of their deep nonpolar, chiral cavities, the two enantiomers of C[4]BINOLs demonstrated exceptionally high recognition affinities (up to 1012 M-1) for 16 important steroidal compounds as well as good enantioselectiviy (up to 15.5) in aqueous solutions, establishing them as the most potent known steroid receptors. Harnessing their ultrahigh affinity, remarkable enantioselectivity, and fluorescence emission properties, the two C[4]BINOL enantiomers were employed to compose a fluorescent sensor array which achieved discrimination and sensing of 16 structurally similar steroids at low concentrations.

Expanding the Hydrophobic Cavity Surface of Azocalix[4]arene to Enable Biotin/Avidin Affinity with Controlled Release.

The development of artificial receptors that combine ultrahigh-affinity binding and controllable release for active guests holds significant importance in biomedical applications. On one hand, a complex with an exceedingly high binding affinity can resist unwanted dissociation induced by dilution effect and complex interferents within physiological environments. On the other hand, stimulus-responsive release of the guest is essential for precisely activating its function. In this context, we expanded hydrophobic cavity surface of a hypoxia-responsive azocalix[4]arene, affording Naph-SAC4A. This modification significantly enhanced its aqueous binding affinity to 1013 M-1, akin to the naturally occurring strongest recognition pair, biotin/(strept-)avidin. Consequently, Naph-SAC4A emerges as the first artificial receptor to simultaneously integrate ultrahigh recognition affinity and actively controllable release. The markedly enhanced affinity not only improved Naph-SAC4A's sensitivity in detecting rocuronium bromide in serum, but also refined the precision of hypoxia-responsive doxorubicin delivery at the cellular level, demonstrating its immense potential for diverse practical applications.

Active targeting tumor therapy using host-guest drug delivery system based on biotin functionalized azocalix[4]arene.

Host-guest drug delivery systems (HGDDSs) provided a facile method for incorporating biomedical functions, including efficient drug-loading, passive targeting, and controlled drug release. However, developing HGDDSs with active targeting is hindered by the difficult functionalization of popular macrocycles. Herein, we report an active targeting HGDDS based on biotin-modified sulfonated azocalix[4]arene (Biotin-SAC4A) to efficiently deliver drug into cancer cells for improving anti-tumor effect. Biotin-SAC4A was synthesized by amide condensation and azo coupling. Biotin-SAC4A demonstrated hypoxia responsive targeting and active targeting through azo and biotin groups, respectively. DOX@Biotin-SAC4A, which was prepared by loading doxorubicin (DOX) in Biotin-SAC4A, was evaluated for tumor targeting and therapy in vitro and in vivo. DOX@Biotin-SAC4A formulation effectively killed cancer cells in vitro and more efficiently delivered DOX to the lesion than the similar formulation without active targeting. Therefore, DOX@Biotin-SAC4A significantly improved the in vivo anti-tumor effect of free DOX. The facilely prepared Biotin-SAC4A offers strong DOX complexation, active targeting, and hypoxia-triggered release, providing a favorable host for effective breast cancer chemotherapy in HGDDSs. Moreover, Biotin-SAC4A also has potential to deliver agents for other therapeutic modalities and diseases.

[Comparison of Pb2+ Adsorption Properties of Biochars Modified Through CO2 Atmosphere Pyrolysis and Nitric Acid].

Acid modification has been widely used to modify the structural properties of biochars. However, acid modification led to the large consumption of acid, increased difficulty of waste effluent disposal, and a high application cost. To evaluate the advantages and application potential of biochars prepared under CO2, utilizing pyrolysis to directly modify biochars to improve heavy metal removal efficiency and reduce production cost, would be an important prerequisite for the broad application of biochars. The sorption performance of Pb2+ with CO2-modified biochars was compared with that of HNO3-modified biochar. The elemental compositions and structural properties of biochars were characterized through elemental analysis, Fourier transform infrared spectroscopy, and X-ray photoelectron spectroscopy. The results revealed that for biochars produced at 500℃, HNO3 modification produced abundant carboxylic groups and -NO2 (asy) and -NO2 (sym) groups, promoting the surface activities and complexing abilities of biochars. The CO2-modified biochars contained abundant carbonate minerals, which could remove Pb2+ by electrostatic ion exchange and coprecipitation or complex. In addition, compared to that of HNO3-modified biochars, CO2-modified biochars had the larger specific surface area and better microporous structures, which were beneficial to the diffusion of Pb2+ and further promoted surface sorption. CO2 modification increased the maximum Pb2+ sorption capacity of W500CO2 and W700CO2, which were 60.14 mg·g-1 and 71.69 mg·g-1. By contrast, HNO3-modified biochars W500N2-A and W700N2-A showed the lower Pb2+ sorption capacities, which were 42.26 mg·g-1 and 68.3 mg·g-1, respectively. The increasing of the specific surface area and functional groups simultaneously promoted the sorption capacity of CO2-modified biochars. Consequently, the CO2-modified biochar had the advantages of low cost, environmental friendliness, and high heavy metal removal efficiency, which is a modification method worthy of promotion and application.

Adaptive and Ultrahigh-Affinity Recognition in Water by Sulfated Conjugated Corral[5]arene.

The pursuit of synthetic receptors with high binding affinities has long been a central focus in supramolecular chemistry, driven by their significant practical relevance in various fields. Despite the numerous synthetic receptors that have been developed, most exhibit binding affinities in the micromolar range or lower. Only a few exceptional receptors achieve binding affinities exceeding 109  M-1 , and their substrate scopes remain rather limited. In this context, we introduce SC[5]A, a conjugated corral-shaped macrocycle functionalized with ten sulfate groups. Owing to its deep one-dimensional confined hydrophobic cavity and multiple sulfate groups, SC[5]A displays an extraordinarily high binding strength of up to 1011  M-1 towards several size-matched, rod-shaped organic dications in water. Besides, its conformation exhibits good adaptability, allowing it to encapsulate a wide range of other guests with diverse molecular sizes, shapes, and functionalities, exhibiting relatively strong affinities (Ka =106 -108  M-1 ). Additionally, we've explored the preliminary application of SC[5]A in alleviating blood coagulation induced by hexadimethrine bromide in vitro and in vivo. Therefore, the combination of ultrahigh binding affinities (towards complementary guests) and adaptive recognition capability (towards a wide range of functional guests) of SC[5]A positions it as exceptionally valuable for numerous practical applications.

A Chiral Emissive Conjugated Corral for High-Affinity and Highly Enantioselective Recognition in Water.

Accurately distinguishing between enantiomeric molecules is a fundamental challenge in the field of chemistry. However, there is still significant room for improvement in both the enantiomeric selectivity (KR(S) /KS(R) ) and binding strength of most reported macrocyclic chiral receptors to meet the demands of practical application scenarios. Herein, we synthesized a water-soluble conjugated tubular host-namely, corral[4]BINOL-using a chiral 1,1'-bi-2-naphthol (BINOL) derivative as the repeating unit. The conjugated chiral backbone endows corral[4]BINOL with good fluorescent emission (QY=34 % ) and circularly polarized luminescence (|glum | up to 1.4×10-3 ) in water. Notably, corral[4]BINOL exhibits high recognition affinity up to 8.6×1010  M-1 towards achiral guests in water, and manifested excellent enantioselectivity up to 18.7 towards chiral substrates, both of which represent the highest values observed among chiral macrocycles in aqueous solution. The ultrastrong binding strength, outstanding enantioselectivity, and facile accessibility, together with the superior fluorescent and chiroptical properties, endow corral[4]BINOL with great potential for a wide range of applications.

[Carbon Loss During Preparation and Aging of Sludge Livestock Manure Biochars].

Biochar has high carbon stability and is a good carbon sequestration material. Sludge biochar is rich in inorganic minerals, which would provide enrichment in the preparation process of pyrolysis, affecting its carbon sequestration capacity in practice. In this study, municipal sludge biochar (SZB), pharmaceutical sludge biochar (YCB), and chicken manure biochar (JFB) were prepared under the pyrolysis process at 500, 600, and 700℃, respectively, and their aging process in soil for 70-100 years was simulated. The physicochemical properties and the carbon loss calculation of the biochars were determined using elemental analysis, FTIR, XRF, ICP, and XRD. The results demonstrated that the type and mass fraction of endogenous minerals in the biochars determined their carbon loss during pyrolysis. Ca and Mg were the main carbon-protecting minerals, whereas Fe may have reduced the carbon stability of the sludge biochars and therefore increased the carbon loss. For the aging process, the stability of the endogenous carbon in the biochars played a major role in its carbon loss, whereas the endogenous minerals played a supporting role. These findings elucidated the effect of the stability of endogenous carbon and the composition of mineral components on the carbon loss of biochars, which may provide references for soil carbon sequestration using sludge and chicken manure biochar.

Geniposide inhibits SphK1 membrane targeting to restore macrophage polarization balance in collagen-induced arthritis mice.

Imbalance of macrophage polarization plays a critical role in the progression of rheumatoid arthritis (RA). Geniposide (GE) has been shown to exert anti-inflammatory effects. However, the effect of GE on macrophage polarization remains unclear. Here, we investigated the regulation of GE on the imbalance of macrophage polarization in RA and how it functions. We established a mouse model of collagen-induced arthritis (CIA) and isolated bone marrow-derived macrophages (BMDMs). The results confirmed that pro-inflammatory M1 macrophages were dominant in CIA mice, but the polarization imbalance of macrophages was restored to a certain extent after GE treatment. Furthermore, the membrane targeting of sphingosine kinase 1 (SphK1) was increased in BMDMs of CIA mice, as manifested by increased membrane and cytoplasmic expression of p-SphK1 and high secretion level of sphingosine-1-phosphate (S1P). RAW264.7 cells were stimulated with lipopolysaccharide (LPS)-interferon (IFN)-γ or interleukin (IL)-4 to induce M1 or M2 phenotype, respectively, to revalidate the results obtained in BMDMs. The results again observed SphK1 membrane targeting in LPS-IFN-γ-stimulated RAW264.7 cells. Selective inhibition of SphK1 by PF543 or inhibition of the S1P receptors by FTY720 both restored the proportion of M1 and M2 macrophages in LPS-IFN-γ-stimulated RAW264.7 cells, confirming that SphK1 membrane targeting mediated a proportional imbalance in M1 and M2 macrophage polarization. In addition, GE inhibited SphK1 membrane targeting and kinase activity. Taken together, results confirmed that the inhibition of SphK1 membrane targeting by GE was responsible for restoring the polarization balance of macrophages in CIA mice.

Metabonomic analysis of abnormal sphingolipid metabolism in rheumatoid arthritis synovial fibroblasts in hypoxia microenvironment and intervention of geniposide.

Rheumatoid arthritis (RA) is a chronic inflammatory disease characterized by a joint hypoxia microenvironment. Our previous untargeted metabolomics study found that sphingolipid (SPL) metabolism was abnormal in the joint synovial fluid samples from adjuvant arthritis (AA) rats. Geniposide (GE), an iridoid glycoside component of the dried fruit of Gardenia jasminoides Ellis, is commonly used for RA treatment in many Asian countries. At present, the mechanism of GE in the treatment of RA, especially in the joint hypoxia microenvironment, is not entirely clear from the perspective of SPL metabolism. The purpose of this research was to explore the potential mechanism of abnormal SPL metabolism in RA joint hypoxia microenvironment and the intervention effect of GE, through the untargeted metabolic analysis based on the ultra-performance liquid chromatography-quadrupole time-of-flight mass spectrometry (UPLC-Q-TOF/MS). Arthritis index, foot swelling and histopathology were used to assess whether the AA rat model was successfully established. The SPLs extracts collected from AA rats' synovial tissue, serum and rheumatoid arthritis synovial fibroblasts (RASFs, MH7A cells, hypoxia/normoxia culture) were analyzed by metabolomics and lipdomics approach based on UPLC-Q-TOF/MS, to identify potential biomarkers associated with disorders of GE regulated RA sphingolipid metabolism. As a result, 11 sphingolipid metabolites related to RA were screened and identified. Except for galactosylceramide (d18:1/20:0), GE could recover the change levels of the above 10 sphingolipid biomarkers in varying degrees. Western blotting results showed that the changes in ceramide (Cer) level regulated by GE were related to the down-regulation of acid-sphingomyelinase (A-SMase) expression in synovial tissue of AA rats. To sum up, this research examined the mechanism of GE in the treatment of RA from the perspective of SPL metabolism and provided a new strategy for the screening of biomarkers for clinical diagnosis of RA.

[Systematic review and sequential analysis of Xuebijing Injection in treatment of systemic inflammatory response syndrome].

To systematically review the efficacy of Xuebijing Injection combined with western medicine in the treatment of systemic inflammatory response syndrome(SIRS). In this study, CBM, CNKI, Wanfang, VIP, PubMed and EMbase databases were retrieved for clinical randomized controlled trials on the effect of Xuebijing Injection combined with western medicine in the treatment of SIRS from the establishment of the database to July 31, 2020. After screening, Meta-analysis was conducted by RevMan 5.3 software, trial sequential analysis was conducted by TSA 0.9.5.10 beta software, and the evidence quality level was evaluated by GRADEprofiler 3.6.1 software. Meta-analysis showed that Xuebijing Injection combined with western medicine could reduce white blood cell count(MD=-2.32, 95%CI[-2.44,-2.21], P<0.000 01), C-reactive protein count(MD=-22.70, 95%CI[-29.61,-15.79], P<0.000 01), APACHE Ⅱ score(MD=-2.15, 95%CI[-2.43,-1.87], P<0.000 01), tumor necrosis factor alpha count(SMD=-1.23, 95%CI[-1.48,-0.99], P<0.000 01) and interleukin-6 count(SMD=-0.92, 95%CI[-1.15,-0.69], P<0.000 01), improve treatment efficiency(RR=1.39, 95%CI[1.23, 1.56], P<0.000 01), reduce incidence of multiple organ dysfunction(RR=0.47, 95%CI[0.35, 0.64], P<0.000 01) and mortality(RR=0.22, 95%CI[0.13, 0.37], P<0.000 01), which were better than western medicine treatment alone. Trial sequential analysis showed that in terms of reducing the incidence of multiple organ dysfunction and C-reactive protein count, the cumulative Z value passed through the traditional threshold, TSA threshold and expected information value, and reached the required number of cases. GRADE evaluation showed that the level of evidence was low or very low. According to the findings, Xuebijing Injection combined with western medicine is effective in treating SIRS. However, as the low quality of the included studies may affect the reliability of the conclusion, more high-quality studies shall be included for further verification in the future, so as to provide better suggestions for clinical medication.

Visible-Light Photoredox-Catalyzed Sulfonyl Lactonization of Alkenoic Acids with Sulfonyl Chlorides for Sulfonyl Lactone Synthesis.

A visible-light photoredox-catalyzed sulfonyl lactonization of unsaturated carboxylic acids with sulfonyl chlorides is described. This reaction features good functional group tolerance and a broad substrate scope, providing a simple and efficient protocol to access a wide range of sulfonyl lactones in high to excellent yields. Preliminary mechanistic investigations suggested that a free-radical pathway should be involved in the process.

Copper-Catalyzed Intermolecular C(sp2)-H Amination with Electrophilic O-Benzoyl Hydroxylamines.

A copper-catalyzed intermolecular electrophilic amination of benzamides with O-benzoyl hydroxylamines was achieved with the assistance of an 8-aminoquinolyl group. With this protocol, good compatibility was observed for a variety of aryl amides and heteroaryl amides, and excellent tolerance with various functional groups was achieved. Significantly, the monoaminated product was overwhelmingly delivered under the simple reaction conditions. Preliminary mechanistic investigations suggested that a radical pathway should be excluded and C-H activation be potentially the rate-determining step.

[Migration and Environmental Effects of Heavy Metals in the Pyrolysis of Municipal Sludge].

Migration characteristics of the heavy metals Fe, Zn, Mn, and Ni during the preparation of biochar from municipal sludge were studied, and the optimal pyrolysis temperature for the preparation of biochar was determined based on potential environmental risks. Four heavy metals (Fe, Zn, Mn, and Ni) with high total contents in the biochar were selected to determine their species and content changes under different pyrolysis temperatures using the BCR extraction method. An environmental risk assessment for sludge-based biochar was also carried out using the potential ecological risk index (PERI) and risk assessment code (RAC). The results showed that the volatility of the four metals is ranked as follows:Zn>Mn>Fe>Ni. The distribution and transformation of the four metal species were different, but their migration paths shared similar characteristics. In the pyrolysis stage at low temperatures (<500℃), unstable fractions gradually changed into more stable species; under high temperatures (>500℃), some of the oxidizable and residual fractions were broken, which transformed into reducible fractions, and other fractions escaped into the atmosphere. In the environmental risk assessment, biochar prepared under high pyrolysis temperatures (>500℃) showed lower environmental risks, with the best outcomes at 500℃.

[Long-term Stability of Aerobic Granular Sludge Under Low Carbon to Nitrogen Ratio].

Long-term stability is important for the practical application of aerobic granular sludge system under low carbon to nitrogen ratio (C/N). In this study, aerobic granular sludge, seeded in the reactors A and B, were cultivated under low C/N to investigate the properties, performance, and resilience to shock load in the long-term operation. The load of carbon and nitrogen in the feed was increased gradually. The C/N of reactor A was kept at 2, while that of reactor B was kept at 4 initially and then reduced to 2 in the shock load stage. It was discovered that the aerobic granular sludge stored at 4℃ for 30 days was essentially revived after 25 days of cultivation in reactors A and B, with over 90% removal efficiency for COD and ammonia, respectively. In the following stages, the removal efficiencies of COD and ammonia in reactor B were over 90% and complete nitrification was achieved. In contrast, in reactor A, the removal efficiency of COD was only 80% and only partial nitrification was achieved; however, ammonia removal efficiency of 90% was finally achieved. In the shock load stage, the COD removal efficiencies in reactors A and B were still above 80%, but the ammonia removal efficiencies were severely affected. The removal of ammonia was deteriorated in reactor A, while only partial nitrification was achieved in reactor B. During the entire operation, the physical properties of the aerobic granules in reactors A and B were barely affected, with sludge volume index (SVI30) in reactors A and B maintained at 60 mL ·g-1 and 75 mL ·g-1, and mixed liquid suspended solid (MLSS) at 5 g ·L-1and 3.7 g ·L-1, respectively. Microbial analysis showed that the aerobic granular sludge in reactor B has richer and more diverse microbial community than that in reactor A. The abundance of Zoogloea in reactor B, which is simultaneously able to produce polymeric protein and stabilize the structure of the aerobic granules, may be favorable for the high stability of the aerobic granules. These findings suggested that the aerobic granular system under the C/N of 4 had better performance in ammonia removal and higher tolerance to shock load, which guaranteed high stability of the aerobic granular sludge system in long-term operation, as compared to that under the C/N of 2.

Reconsideration of the plague transmission in perspective of multi-host zoonotic disease model with interspecific interaction.

The human-animal interface plays a vital role in the spread of zoonotic diseases, such as plague, which led to the "Black Death", the most serious human disaster in medieval Europe. It is reported that more than 200 mammalian species including human beings are naturally infected with plague. Different species acting as different roles construct the transmission net for Yersinia pestis (plague pathogen), in which rodents are the main natural reservoirs. In previous studies, it focused on individual infection of human or animal, rather than cross-species infection. It is worth noting that rodent competition and human-rodent commensalism are rarely considered in the spread of plague. In order to describe it in more detail, we establish a new multi-host mathematical model to reflect the transmission dynamics of plague with wild rodents, commensal rodents and human beings, in which the roles of different species will no longer be at the same level. Mathematical models in epidemiology can clarify the interaction mechanism between plague hosts and provide a method to reflect the dynamic process of plague transmission more quickly and easily. According to our plague model, we redefine the environmental capacity K with interspecific interaction and obtain the reproduction number of zoonotic diseases RZ0, which is an important threshold value to determine the zoonotic disease to break out or not. At the same time, we analyze the biological implications of zoonotic model, and then study some biological hypotheses that had never been proposed or verified before.

Dynamic behavior of swine influenza transmission during the breed-slaughter process.

Global influenza pandemics have brought about various public health crises, such as the 2009 H1N1 swine flu. Actually, most swine influenza infections occur during the breed-slaughter process. However, there is little research about the mathematical model to elaborate on the swine influenza transmission with human-pig interaction. In this paper, a new breed-slaughter model with swine influenza transmission is proposed, and the equilibrium points of the model are calculated subsequently. Meanwhile, we analyze the existence of the equilibrium points by the persistence theory, and discuss their stability by the basic reproduction number. And then, we focus on the invasion process of infected domestic animals into the habitat of humans. Under certain conditions as in Theorem 2, we construct a propagating terrace linking human habitat to animal-human coexistent habitat, then to swine flu natural foci, which is divided by spreading speeds.

A host-guest drug delivery nanosystem for supramolecular chemotherapy.

Supramolecular chemotherapy is currently a new strategy to improve the therapeutic efficacy as well as overcome the side effects of traditional chemotherapy. Herein, a supramolecular chemotherapy platform based on the pegylated guanidinium-modified calix[5]arene pentadodecyl ether (GC5A-12C) nanoassembly was prepared. Three commercially available antitumor drugs: oxaliplatin, methotrexate and chlorambucil, all showed strong binding to this GC5A-12C nanocarrier. The supramolecular nanodrugs achieved higher anticancer performances compared with free drugs in cell experiments. Furthermore, the cellular uptake mechanisms and efficacy are confirmed by fluorescence imaging.

A hyaluronidase/ATP tandem stimuli-responsive supramolecular assembly.

We designed a tandem stimuli-responsive assembly based on a guanidinium-modified calix[5]arene (GC5A-6C) and eosin Y modified hyaluronic acid (EY-HA), which showed hyaluronidase-triggered disassembly and ATP-activated release of EY. Both hyaluronidase and ATP are tumor biomarkers, and therefore, the present system shows potential in precision delivery with respect to tumor phototheranostics.

Copper(II)-Catalyzed Alkene Aminosulfonylation with Sodium Sulfinates For the Synthesis of Sulfonylated Pyrrolidones.

A copper-catalyzed direct aminosulfonylation of unactivated alkenes with sodium sulfinates for the efficient synthesis of sulfonylated pyrrolidones is described. This reaction features good functional group tolerance and wide substrate scope, providing an efficient and straightforward protocol to access this kind of pyrrolidones. Moreover, preliminary mechanistic investigations disclosed that a free-radical pathway might be invovled in the process.